Iontophoretic drug delivery device and reservoir and method of making same

ABSTRACT

A reservoir electrode assembly of the present invention for an iontophoretic drug delivery device includes an electrode and a hydrophilic reservoir situated in electrically conductive relation to the electrode. The hydrophilic reservoir is formed from a bibulous hydrophilic cross-linked polymeric material having a first surface and a second surface that is adhesively adherent to the electrode. The first surface of the polymeric material is releasably adhesively adherent when applied to an area of a patient&#39;s skin. The polymeric material has a cohesive strength forms an adhesive bond with a bond strength between the second surface of the polymeric material to the electrode that is greater than the cohesive strength of the polymeric material. Additionally, an adhesive bond strength of the first surface of the polymeric material to the applied area of the patient is less than the cohesive strength of the polymeric material so that upon removal of the reservoir assembly of the invention from the applied area of the patient, substantially no polymeric material remains on the applied area and the hydrophilic reservoir remains substantially intact and adhesively adherent to the electrode.

This application is a continuation-in-part of application Ser. No.08/533,979 filed Sep. 26, 1995, which is a continuation-in-part ofapplication Ser. No. 08/129,222 filed Sep. 30, 1993, now abandoned.

FIELD OF THE INVENTION

The present invention generally relates to iontophoretic systems fordelivering medicaments such as therapeutic drugs and medicines topatients transdermally, i.e., through the skin, and more specificallyrelates to a stable iontophoretic drug delivery device and a reservoirfor use in the same. In addition, the present invention relates to amethod for making a stable iontophoretic drug delivery device with longshelf life and the reservoir for use in such a device.

BACKGROUND

Transdermal drug delivery systems have, in recent years, become anincreasingly important means of administering drugs. Such systems offeradvantages clearly not achievable by other modes of administration suchas avoiding introduction of the drug through the gastrointestinal tractor punctures in the skin to name a few.

Presently, there are two types of transdermal drug delivery systems,i.e., “Passive” and “Active.” Passive systems deliver drug through theskin of the user unaided, an example of which would involve theapplication of a topical anesthetic to provide localized relief, asdisclosed in U.S. Pat. No. 3,814,095 (Lubens). Active systems on theother hand deliver drug through the skin of the user, such as a patient,using iontophoresis, which according to Stedman's Medical Dictionary, isdefined as “the introduction into the tissues, by means of an electriccurrent, of the ions of a chosen medicament.”

Conventional iontophoretic devices, such as those described in U.S. Pat.No. 4,820,263 (Spevak et al.), U.S. Pat. No. 4,927,408 (Haak et al.) andU.S. Pat. No. 5,084,008 (Phipps), the disclosures of which are herebyincorporated by reference, for delivering a drug or medicinetransdermally through iontophoresis, basically consist of twoelectrodes—an anode and a cathode. Usually, electric current is drivenfrom an external supply into the skin at the anode, and back out at thecathode. Accordingly, there has been considerable interest iniontophoresis to perform delivery of drugs for a variety of purposes.Two such examples, involve the use of Novocaine,™ which is usuallyinjected prior to dental work to relieve pain, and Lidocaine,™ which isusually applied as a topical, local anesthetic.

Such prior devices have prior hereto not been pre-loaded and selfadhering, e.g., they have typically utilized an absorbent pad or poroussolid sheet that can be filled with drug solution as the drug reservoir.These absorbent pads or porous sheets have three major disadvantages.First, they must be filled with the drug solution after removal from thepackage since these pads or porous sheets do not hold the drug solutionas the solution is subject to removal and leakage under pressure orflexure. In addition, even after the inconvenient addition of the drugsolution and after removal from the package, the absorbent pad or poroussheet reservoir remain subject to leakage and smearing of the drugsolution due to pressure or flexure upon the skin. Furthermore,absorbent pads or porous solid sheets can not provide the electricalcontinuity to complete intimate contact since they lack adhesiveness andflexibility with the skin and its contours.

In addition, prior drug reservoirs have included pastes and unformedviscous semi-solid gels such as for example agar that have both solidand liquid characteristics as described, for example, in U.S. Pat. No.4,383,529 (Webster), the disclosure of which is hereby incorporated byreference.

Powers et al., U.S. Pat. No. 4,886,277, although suggesting thatLidocaine could be incorporated into the reservoir, fails to solve theresulting problem associated with compatibility with adjacent materialssuch as conductive layers. Accordingly, such a device would fail toprovide sufficient stability for extended shelf life, i.e., more thanone year.

However, several disadvantages and limitations have been associated withthe use of such devices, including handleability and loadability. Forexample, the semi-solid agar reservoir disclosed in Webster flows undershear or stress. Furthermore, this disclosed reservoir may melt uponexposure to modest elevated temperatures. The agar is unstable,spontaneously releasing aqueous solution.

Thus, there has been a need for an iontophoretic drug delivery deviceand a reservoir for use in the same, as well as a method for making thereservoir, which would eliminate the problems and limitations associatedwith the prior devices discussed above, most significant of the problemsbeing associated with stability, handleability, loadability andelectrocontinuity of the reservoir, including chemical and thermalstability of the reservoir and the electrode.

SUMMARY

A reservoir electrode assembly of the present invention for aniontophoretic drug delivery device includes an electrode and ahydrophilic reservoir situated in electrically conductive relation tothe electrode. The hydrophilic reservoir is formed from a bibuloushydrophilic cross-linked polymeric material having a first surface and asecond surface that is adhesively adherent to the electrode. The firstsurface of the polymeric material is releasably adhesively adherent whenapplied to an area of a patient's skin. The polymeric material has acohesive strength forms an adhesive bond with a bond strength betweenthe second surface of the polymeric material to the electrode that isgreater than the cohesive strength of the polymeric material.Additionally, an adhesive bond strength of the first surface of thepolymeric material to the applied area of the patient is less than thecohesive strength of the polymeric material so that upon removal of thereservoir assembly of the invention from the applied area of thepatient, substantially no polymeric material remains on the applied areaand the hydrophilic reservoir remains substantially intact andadhesively adherent to the electrode.

The reservoir electrode of the present invention provides solutions forseveral problems seen with available iontophoretic reservoir electrodes.The reservoir electrode of the invention, by being adherent to the skinof the patient minimizes current pathway concentrations that oftenresult in irritation and burning caused by incomplete contact of thereservoir electrode assembly to the patient's skin. Because the adhesivebond of the electrode to the patient's skin is less than the cohesivestrength of the polymeric material used for the reservoir, substantiallyno residue from the reservoir material is left behind on the patient'sskin. Additionally, since the polymeric reservoir material forms anadhesive bond with the electrode, there is intimate and effectiveelectrical contact between the electrical circuit and the polymericreservoir material. The reservoir electrode assembly of the inventioncan be physically smaller than most currently available electrodeassemblies because the entire polymeric reservoir is hydrophilic and isutilized to contain drugs and electrolytes. Many current electrodeassemblies require hydrophobic polymeric materials to achieve anadhesive tack and another hydrophilic material to retain the aqueousdrug and electrolyte used for the iontophoretic delivery. When ahydrophobic and a hydrophilic component are used to form a reservoir, asin the currently available materials, some partitioning of themedicament may occur or there may be some binding of the active compoundwith the hydrophobic material that reduces the availability of themedicament for delivery. These effects are not seen with the hydrophilicreservoir of the invention.

In contrast to the prior devices discussed above, it has been found thata iontophoretic drug delivery device particularly suited for use todeliver at least one medicament, particularly in a high dose efficiency,can be constructed in accordance with the present invention by theincorporation of an aqueous swollen cross linked water soluble polymericdrug delivery reservoir adhesively coupled to the electrode such thatthe adhesive strength of the electrode material is greater than thecohesive strength of the reservoir material. In addition, the device ofthe present invention can easily fit over any contour of the body andprovide excellent electrocoupling with the electrode and the skin, whilestill being capable of flexing and adhering to the skin. Also the deviceof the present invention can be applied over a range of temperatures andis stable for over one year at controlled room temperature to provide acommercially advantageous shelf-life.

The iontophoretic drug delivery device of the present invention fordelivering at least one medicament to an applied area of a patient, suchas the skin, mucous membrane and the like, including electrode assemblymeans for driving a medication into the applied area of the patient tobe absorbed by the body of the patient, the electrode include anelectrode material, and a covalently cross linked hydrophilic reservoirsituated in electrically conductive relation to the electrode assemblymeans, with the reservoir including an aqueous swollen cross linkedwater soluble polymer material having an adhesive strength to theelectrode material, an adhesive strength to the applied area and acohesive strength to itself, with the reservoir containing at least onemedicament, wherein the adhesive strength of the polymer material to theelectrode material is greater than the cohesive strength of the polymermaterial and the adhesive strength of the polymer material to theapplied area is less than the cohesive strength of the polymer materialso that upon removal of the device from the applied area little if anypolymer material remains on the applied area, while maintaining thereservoir intact and in intimate contact with the electrode material.

In the preferred embodiment, the device of the invention furtherincludes a structurally reinforcing member situated within the reservoirincluding the aqueous swollen cross linked water soluble polymer, withthe structurally reinforcing member having an open area that is thin andof sufficient voidage so as not to impede the flow of ions. in addition,the structurally reinforcing member is a thermoplastic polymeric scrimand the aqueous swollen cross linked water soluble polymer is crosslinkable by high energy irradiation with the scrim being wettable enoughand with open area of greater than 40% to insure phase continuity thoughthe scrim, along with sufficient adhesion to contribute strength to theaqueous cross linked polymeric reservoir. Also, the aqueous swollencross linked water soluble polymer is selected from the group includingpolyethylene oxide, polyvinyl pyrrolidone, polyvinyl alcohol,polyethylene glycol, and polyacrylamide. The at least one medicamentincludes Lidocaine and the reservoir also includes a vasoconstrictor,stabilizers and glycerin. Further, the reservoir further includesadditives and conductive salts, with the additives selected from thegroup including glycerin, propylene glycol, polyethylene glycol andpreservatives.

The reservoir of the present invention for use in an iontophoretic drugdelivery device having an electrode assembly including an electricallyconductive electrode material for delivering at least one medicamentthrough an applied area of a patient, such as the skin, mucous membraneand the like, includes a layer of a aqueous swollen cross linked watersoluble polymer material capable of having electrocontinuity with theelectrode assembly, with the aqueous swollen cross linked water solublepolymer material having sufficient adhesive tack including the at leastone medicament for delivery through an applied area of a patient, suchas the skin, mucous membrane and the like, and the aqueous swollen crosslinked water soluble polymer material having an adhesive strength to theelectrode material greater than the cohesive strength of the polymermaterial, and the cohesive strength being greater than an adhesivestrength to the applied area.

In the preferred embodiment, the reservoir also includes a structurallyreinforcing member situated within the layer of aqueous swollen crosslinked water soluble polymer material, with the structurally reinforcingmember having approximately 40% porosity so as not to impede the flow ofions, with the structurally reinforcing member being a wettable, scrimof a aqueous insoluble thermoplastic polymeric material and the aqueousswollen cross linked water soluble polymer material is cross linked byhigh energy irradiation. Also, aqueous swollen cross linked watersoluble polymer is selected from the group including polyethylene oxide,polyvinyl pyrrolidone, polyvinyl alcohol, polyacrylamide andpolyethylene glycol. In addition, the at least one medicament includesLidocaine and the aqueous swollen cross linked water soluble polymermaterial includes a vasoconstrictor, stabilizers and glycerin. Further,the reservoir includes additives and conductive salts, with theadditives selected from the group including glycerin, propylene glycoland polyethylene glycol and preservatives.

The method of making a reservoir for an iontophoretic drug deliverydevice of the present invention includes the steps of providing astructurally reinforcing member, coating the reinforcing member with aviscous water soluble polymer solution on both sides of the structurallyreinforcing member such that the polymer solution penetrates the openarea, wets the reinforcing member, and cross linking the layer by highenergy irradiation, with the cross-linked layer of polymer having anadhesive strength to an electrode material greater than a cohesivestrength of the polymer, and the cohesive strength being greater than anadhesive strength to an applied area.

In the preferred embodiment of the method, the step of coating includesthe steps of applying a layer of the viscous solution to one side of thereinforcing member, applying a layer of the viscous solution to one sideof a release liner and laminating the release liner and the reinforcingmaterial together such that both surfaces of the reinforcing member arecoated with the viscous solution. In addition, the viscous solution isapplied to the reinforcing member and the release liner to a thicknessof about Ca. 5 mil to 70 mil. The method also includes the step ofapplying final release liners to the remaining exposed viscous solutioncoated surfaces of the reinforcing member to form a laminate and crosslinking the viscous solution. Also, the method includes the steps ofreplacing one of the final release liners with an electrode in flexiblesheet form, and adding at least one medicament to the cross linked watersoluble polymer, with the at least one medicament includes Lidocaine andthe cross linked water soluble polymer includes a vasoconstrictor,stabilizers, glycerin and preservative. Further, the method includes theof cutting the laminate into a suitable shape and area and laminating itto a conductive metal for use in an iontophoretic drug delivery device.

BRIEF DESCRIPTION OF THE DRAWINGS

The various features, objects, benefits, and advantages of the presentinvention will become more apparent upon reading the following detaileddescription of the preferred embodiment along with the appended claimsin conjunction with the drawings, wherein like reference numeralsidentify corresponding components, and:

FIG. 1 is a schematic view of the iontophoretic drug delivery device ofthe present invention illustrating placement of the device on a user;

FIG. 2 is a cross sectional view of the device of the present invention;

FIGS. 3A, 3B, 3C and 3D are schematic views of the various steps of themethod for making the reservoir of the present invention;

FIG. 4 is a logic flow diagram depicting the various steps of the methodfor making the reservoir of the present invention;

FIG. 5 is a cross-sectional view of the reservoir electrode assembly ofthe invention;

FIG. 6 is a schematic perspective view of the reservoir of the inventionfrom FIG. 5;

FIG. 7 is a schematic cross-sectional view of the coating andcross-linking of the web for forming the PVP reservoir; and

FIG. 8 is a schematic top plan view of the web illustrating punching outindividual reservoir units.

DETAILED DESCRIPTION

The iontophoretic drug delivery device of the present invention isillustrated in FIGS. 1 and 2, and generally includes the designation 10.Referring to FIGS. 1 and 2, the device 10 of the present inventionincludes an electrode assembly 12, having at least one electrode and atleast one reservoir, with the reservoir and electrode held or containedwithin a suitable structure 16, with a skin adhesive 18. Also, as iswell known in the art, a power source 19 is provided in circuit with theelectrode assembly 12 for supplying a source of electrical current. Itshould be appreciated that a return electrode and reservoir may becombined into a single electrode assembly 12 or separately provided asillustrated in FIG. 1.

In the preferred embodiment, the device is divided or otherwiseseparated into two portions 20 and 22, with the electrode assembly 12including two electrodes 24 and 26. One portion 20 (first) includes theelectrode 24 and a reservoir 28, with the reservoir being situatedadjacent and coupled to the electrode 24 and holding at least onemedicament or drug 30, preferably in ionized or ionizable forms, to bedelivered iontophoretically. The other portion 22 (second) includes theelectrode 26 and a reservoir 32, with the reservoir being situatedadjacent to the electrode 26 and holding an electrolyte 34. Theparticular electrolyte is not essential to the present invention and ismerely a matter of choice. However, in this embodiment the electrolytemay include sodium chloride in an aqueous solution, matrix or the likeas explained in greater detail hereinbelow.

A schematic diagram of the first portion 20 of the device 10 isillustrated in FIG. 2. In this case, the medicament 30 to be deliveredthrough the skin is a cation and the reservoir 28 is connected to theelectrode 24, which acts as an anode. The return electrode 26 (cathode)may be constructed in the manner as the working electrode 24. If thedrug is an anion, then the drug containing reservoir would be connectedto the cathode and the return reservoir would be connected to the anode.

As is well known within the field, the device can be situated on thearea of the patient to which the medicament is to be applied (theapplied area) and a voltage impressed across the electrodes 24, 26 ofthe electrode assembly 12 to cause current to flow through the skin 60of the patient to drive the ionic medicament locally into the skin andthe tissue or to be absorbed systematically by the body of the patient.It should also be appreciated that the device of the present inventioncan be applied to other areas of the body such as mucous membranes andthe like depending upon the desired therapy and medicaments to bedelivered.

In order to transport the medicament through intact skin 60 at least thereservoir 28 containing the medicament includes an aqueous swollen crosslinked water soluble polymer, which for simplicity is hereinafterreferred to as a cross linked water soluble polymer. The cross linkedwater soluble polymer can be incorporated into the reservoir as ahomogeneous solid cut or molded sheet 40 of suitable shape and areawhich can be attached to the electrode as illustrated in FIGS. 1 and 2.However, it should be appreciated that the reservoir 32 (cathode) mayalso be made of the same material as the reservoir 28 containing themedicament, i.e., to include the cross linked water soluble polymersheet 40 illustrated in FIGS. 3A-3D. Accordingly, the cross linked watersoluble polymer sheet 40 containing either the medicament and/or theelectrolyte serves as the reservoirs 28, 32 and the electrical couplingto the skin while being able to conform to all contours of the body. Inaddition, the reservoir may include additives selected from the groupincluding glycerin, propylene glycol, polyethylene glycol and conductivesalts, as well as preservatives.

The particular cross linked water soluble polymer material may be madefrom a variety of commercially available water soluble polymers known tothose skilled in the art as long as it is of low bioburden, iselectrically conductive, readily conforms to the contours of the body,is capable of being cross linked and can hold or otherwise retain thedrug solution under pressure and flexure.

Cross linked water soluble polymers are preferred reservoirs as theyprovide a conformable interface with good electrical coupling andexcellent biocompatibility. Examples of such cross linked water solublepolymers are irradiated cross linked polyethylene oxide (PEO), polyvinylpyrrolidone (PVP), polyvinyl alcohol (PVA), polyethylene glycol (PEG),polyacrylamide and polyethylene glycol (PEG). The cross linked watersoluble polymer sheet 40 by nature of its preparation by irradiationcross linking is of low bioburden and is non toxic, non irritating andnon sensitizing to the skin. This is particularly assured by the factthat no chemical cross linking agents or organic solvents are requiredto synthesize the cross linked water soluble polymer material. It shouldbe appreciated, that the techniques of irradiation cross linking thewater soluble polymer material are well known in the art.

In the preferred embodiment, the cross linked water soluble polymersheet 40 may include a netting or non-woven material 42 such as an inertand wetable polyethylene terphthalate (PET) material is the form of ascrim commercially available from Reemay, Inc. The scrim utilized forthis application is preferably an open web, inert, water insolublematerial that does not change the conductivity or ionic flow of thematerials in the water soluble polymer. In addition, the scrim iswetable and porous. The basis weight of the scrim being of a basisweight between Ca. 4 to 60 grams/square yard. Also, in this way, thecross linked water soluble polymer sheet 40 can be formed from asolution 44 of pre-mixes after dispersion and full solution, with thesolution then applied on both sides of the scrim 42 to a thickness ofCa. 5 mil to 40 mil and then cross linked by high energy irradiationsuch as for example, electron beam or gamma irradiation to form covalentcross links. The particular thickness of the cross linked water solublepolymer sheet may vary depending upon, e.g., the medicament to bedelivered, the applied area and the like, from a very thin sheet, i.e.,film, for high drug efficiency to a very thick sheet for minimization ofsensation when an electrical current is applied. However it should alsobe appreciated that suitable scrim materials may include inorganicmaterials such as ceramics and composites such as fiber glass.

As illustrated in FIGS. 3A, 3B, 3C and 3D, and the flow diagramillustrated in FIG. 4, preferably the cross linked water soluble polymersheet 40 is formed by providing the release liner 46 and the scrim 42,applying or otherwise coating a release liner or other backing material46 with one-half of the viscous solution 44 of water soluble polymer toform a layer 44A (FIG. 3B) and coating or otherwise applying the otherhalf of the viscous solution 44 to one side of the scrim 42 to form alayer 44B (FIG. 3C). The coated liner 46 is then laminated to the coatedscrim 42 such that the scrim has the viscous solution on both sides(FIG. 3D). Next, a final liner or other backing material 48 is thenapplied to the exposed surface, with the cross linked water solublepolymer sheet 40 sandwiched between the two release liners 46, 48 toform a laminate 50, which in the preferred embodiment is then exposed tohigh energy irradiation to cross link the water soluble polymersolution. In the alternative, to provide ease of handling, the finalrelease liner 48 can be applied to the coated scrim prior to laminationwith the coated liner 46.

The scrim 42 itself imparts structural support and mechanical strengthto the final cross linked water soluble polymer sheet to preventshearing. Thereafter, the laminate 50 can be easily handled and cut orotherwise formed into the desired shape for the particular reservoir 28,32. In this way, the release liner 46 can be subsequently removed andthe exposed surface of the cross linked water soluble polymer adhered tothe electrode 24, 26, or removed and the medicament 30 added and therelease liner replaced or adhered to the electrode. Also, the releaseliner 48 can remain until being removed for application of the device 10to the applied area of the patient.

In the alternative, the release liner 48 (or 46) can be replaced by theelectrode in the form of a thin metal sheet or polymer sheet coated witha conductive ink or metal foil laminated to the polymeric sheet such asfor example as disclosed in co-pending application Ser. No. 08/012,168,the disclosure of which is hereby incorporated by reference. In thisway, the reservoir can be coupled to the electrode in one step. Itshould also be appreciated that a conductive scrim may be incorporatedinto the reservoir with the scrim being placed asymmetrically within thereservoir by placing different thicknesses of the viscous solution oneach side of the scrim.

The use of an easily handled cross linked water soluble polymer sheet asthe reservoir 28, 32 to replace a paste, semi-solid gel or an absorbentpad has many advantages over existing coupling reservoirs. The crosslinked water soluble polymer is solid and shape retaining and itexhibits no leakage of medicament or electrolyte under flexure orapplied pressure. It is also drapeable and flexible and adhesive to theskin. This assures that the cross linked water soluble polymer maintainsthe required medicament and electrolyte concentration as well asreproducible delivery by its adherence and conformability to thecontours of the skin or other applied area.

Also, the adhesive strength of the gel and the electrode material isgreater than the cohesive strength of the gel material and the cohesivestrength of the gel is greater than the adhesive strength of the gel tothe applied area, e.g., skin of the patient. In this way, a intimateelectrical contact between the electrode and the reservoir is achievedwhich insures electrical continuity (and uniformity) between theinterface of the electrode and the gel during applications of he deviceto the applied area. Also, upon removal of the device, little, if any,material remains on the applied area after removal of the device.

Due to its high water content, the cross linked water soluble polymer ishighly conductive to ionic transport, yet in combination with the scrim,it possesses sufficient mechanical strength for processing and use.Also, despite its high water content, the cross linked water solublepolymer is a single phase solid solution which does not synerese liquidspontaneously or upon applied pressure or flexure.

The ability of the cross linked water soluble polymer to retain aqueoussolution and its stability over extremes of ambient temperature, allowthe iontophoretic drug delivery device 10 to be prepackaged and storedas a ready to use device, eliminating the need for loading a drugsolution after opening and assembly.

In addition, the various reservoirs 28, 32 formed from the cross linkedwater soluble polymer sheet 40 are easily and stabably coupled with theelectrically conductive electrodes 14, 26 to form a highly electricallyconductive electrode assembly 12. Also, because of the handleability ofthe cross linked water soluble polymer, the medicament can either beadded to the viscous water soluble polymer solution or subsequentlyadded after cross linking depending upon the application and/or themedicament to be administered.

As previously discussed, the two portions of the device 20, 22 areplaced over the applied area, i.e., the portion of the skin where themedicament is to be delivered such as the arm as illustrated in FIG. 1with other electrode 32, i.e., the return electrode, placed on the skin60 at an appropriate location relative to the first or working electrode14.

Further, the cross linked water soluble polymer 40 in the preferredembodiment of the present invention is self-adhering to the skin of thepatient and therefore provides intimate contact for ionic transport.Accordingly, the cross linked water soluble polymer sheet 40 containedin the drug reservoir 28 and used for the electrolyte reservoir 32 mayalso act as an adhesive, eliminating the need in prior devices for anadhesive layer or the like.

The following formulations for the cross linked water soluble polymersheet 40 were used in connection with the device of the presentinvention for the reservoirs in the iontophoretic delivery of a topicalanesthetic and a vasoconstrictor, with the device 10 including oneactive electrode 24 having a surface area between 2-10 cm² and one tothree return electrodes 26 having a total surface area between 1-5 cm².The electrode reservoir 28 was comprised of the following active andinert components to a thickness of between 10-50 mils by making aviscous stock solution containing the medicaments and the excipientsthat was 3 times more concentrated than the intended final formulation.The stock solution was then added to pre-existing sheets as one partsolution to two parts sheet (by weight) and allowed to diffuse andequilibrate in the sheets.

EXAMPLE 1

EXAMPLE 1 Concen- Mass per Active tration 2.5 cm sq Components InertComponents (%, w/w) (mg) Lidocaine hydro- 10.00 45.000 chloride, U.S.P.Epinephrine 0.10 0.450 Bitartrate Glycerin, U.S.P. 10.00 45.000 Crosslinked polyvinyl 16.67 75.020 pyrrolidone (PVP), U.S.P. Sodiummetabisulphite, 0.05 0.230 U.S.P. EDTA disodium, U.S.P. 0.01 0.045Citric acid, U.S.P. 0.02 0.090 Water 63.15 450 Total 100.00 450.000

In the preferred embodiment, the Lidocaine is an anesthetic, theEpinephrine Bitartrate (“Epinephrine”) is a vasoconstrictor, and thecomposition of PVP is 10% to 20%, preferably 15%, known as K-90F fromBASF Corp. However, it should be appreciated that the concentration ofthe PVP may vary from approximately 10% to 60% w/w. In addition, itshould be appreciated that L-Adrenaline can be substituted for theEpinephrine.

After cross-linking the gel material of Example 1 having 25% PVP, 75%water and 1% preservative PHENONIP manufactured NIPA Corporation byexposure to 2 Mrad (20 kGy) and loaded with drug and excipients, it wasfound that this gel material when applied to an electrode comprised ofsilver/silver chloride ink printed onto a polyester substrate, such thatthe surface resistance is less than 3 ohm per square, and the driedcoating is porous yielded an average adhesive strength greater than 40grams/inch which was on average greater than the cohesive strength (peelstrength) of the gel material as evident by gel material tearing apartupon peeling, which remained on the electrode surface. Despite thisrelatively low cohesive strength, it was still sufficiently greater thanthe adhesive strength to the skin as evident by little, if any, gelmaterial remaining on the skin upon removal of the reservoir.

In another, after cross-linking the gel material of Example 1 having 25%PVP, 75% water and 1% preservative PHENONIP manufactured NIPACorporation by exposure to 1.5 Mrad (15 kGy) and loaded with drug andexcipients, it was found that this gel material when applied to anelectrode comprised of silver/silver chloride ink printed onto apolyester substrate, such that the surface resistance is less than 3 ohmper square, and the dried coating is porous yielded an average adhesivestrength greater than 60 grams/inch which was on average greater thanthe cohesive strength (peel strength) of the gel material as evident bygel material tearing apart upon peeling, which remained on the electrodesurface. Despite this relatively low cohesive strength, it was stillsufficiently greater than the adhesive strength to the skin as evidentby little, if any, gel material remaining on the skin upon removal ofthe reservoir.

EXAMPLE 2

Same as Example 1, however, Polyethylene oxide (PEO) NF was substitutedfor the PVP with the unloaded reservoir polymer concentration beingaround 1% to 6%, preferably 5.0%, however, it should be appreciated thatthe concentration of the PEO may varying from approximately 1-10% w/wdepending upon its molecular weight.

Further, material remaining on the electrode is preferred as evidencingintimate contact between the electrode and the reservoir.

EXAMPLE 3

Same as Example 1, with polyvinyl alcohol (PVA) being substituted forthe PVP, and the preferred unloaded reservoir polymer concentration ofthe PVA varying from approximately 10-30% w/w.

EXAMPLE 4

Same as Example 1, with polyethylene glycol (PEG) being substituted forthe PVP, and the preferred unloaded reservoir polymer concentration ofthe PEG varying from approximately 20-60% w/w.

EXAMPLE 5

Same as Example 1, with the addition of about 5-20% glycerin, preferably10%, to the reservoir to keep the aqueous drug solution form diffusinginto all other phases in contact with the reservoir which is definedherein as a “synerisis inhibitor”.

Each of the above applications involved the use of devices for thedelivery of Lidocaine and Epinephrine for short application times, i.e.,less than 30 minutes.

Drug, medication, medicament and active compound have been used hereinto mean any ionicly charged pharmaceutical agent, such as therapeuticcompounds, diagnostic agents and the like.

In addition, it should be appreciated that the device and reservoir ofthe present invention may be packaged in a nitrogen rich environment asdisclosed in co-pending application Ser. No. 08/316,741, the disclosureof which is hereby incorporated by reference.

Further, while the present invention has been described in connectionwith iontophoresis, it should be appreciated that it may be used inconnection with other principles of electroactive introduction, i.e.,motive forces, such as electrophoresis which includes the movement ofparticles in an electric field toward one or other electric pole, anode,or cathode and electro-osmosis which includes the transport of unchargedcompounds due to the bulk flow of water induced by an electric field.Also, it should be appreciated that the patient may include humans aswell as animals.

While the preferred embodiments of the present invention have beendescribed so as to enable one skilled in the art to practice the deviceand method of the present invention, it is to be understood thatvariations and modifications may be employed without departing from theconcept and intent of the present invention as defined in the followingclaims. The preceding description is intended to be exemplary and shouldnot be used to limit the scope of the invention. The scope of theinvention should be determined only by reference to the followingclaims.

While this invention is satisfied by embodiments in many differentforms, there are shown in the drawings and herein described in detail,embodiments of the invention with the understanding that the presentdisclosure to be considered as exemplary of the principles of thepresent invention and is not intended to limit the scope of theinvention to the embodiments illustrated. The scope of the invention ismeasured by the appended claims and the equivalents.

Referring to FIGS. 5-8, a reservoir electrode assembly 110 of thepresent invention for an iontophoretic drug delivery device includes anelectrode 112 and a hydrophilic reservoir 114 situated in electricallyconductive relation to electrode 112. Hydrophilic reservoir 114 isformed from a bibulous hydrophilic cross-linked polymeric material 116having a first surface 118 and a second surface 120 that is adhesivelyadherent to electrode 112. First surface 118 of polymeric material 116is releasably adhesively adherent when applied to an area 122 of apatient's skin. Polymeric material 116 has a cohesive strength and formsan adhesive bond 124 with a bond strength between second surface 120 ofthe polymeric material to electrode 112 that is greater than thecohesive strength of polymeric material 116. Additionally, an adhesivebond strength of first surface 118 of polymeric 116 material to appliedarea 122 of the patient is less than the cohesive strength of polymericmaterial 116 so that upon removal of reservoir assembly of the inventionfrom the applied area of the patient, substantially no polymericmaterial 116 remains on applied area 122 and hydrophilic reservoir 114remains substantially intact and adhesively adherent to electrode 112.

Adverting to FIG. 6, reservoir electrode assembly 110 preferablyincludes a reinforcement 126 to provide two-dimensional stability,indicated by reference characters x and y, to polymeric material 116 andallow a swelling of polymeric material 116 in a third dimension z.Reinforcement 126 may be formed from a woven material or a non-wovenmaterial. Preferably, reinforcement 126 is formed from a non-wovenmaterial with a basis weight about ten to about thirty grams per squaremeter. Reinforcement 126 is preferably disposed in a layer 128substantially intermediate first surface 118 and said second surface 120of bibulous hydrophilic polymeric material 116 so that when polymericmaterial 116 imbibes an aqueous solution, swelling of polymeric material116 is substantially limited to increasing a distance “d” between firstsurface 118 and second surface 120. Preferably, first surface 118 andsecond surface 120 are substantially parallel to each other. Suitablenon-woven materials are available from Reemay as a spun-bondedpoly(ethyleneterephthalate) 2004 (PET) with a basis weight of about 14grams per square meter. Other materials with other basis weights may bepreferred for particular applications and are considered within thescope of this disclosure.

A preferred material for forming hydrophilic reservoir 114 ispoly(vinylpyrollidone) (PVP) with a number average molecular weightgreater than about 360,000 daltons. A suitable PVP is available fromBASF, NJ as PVP K-90F. When this material is prepared as a concentratedaqueous solution it forms a viscous syrup which is preferably applied toboth sides of the reinforcement 126, placed between two release webs toa thickness of about of about 40 mils and subjected to ionizingradiation sufficient to cross-link the PVP sufficiently to substantiallybe shape retaining, flexible and having a degree of tack. A preferredionizing radiation is an electron beam having at least about a 1 MeV todeliver between about 1.5 and 2.5 megarads. Other sources of ionizingradiation such as ⁶⁰Co or ¹³⁷Cs may be used for particular applications.The degree of cross-link has considerable effect on the degree of tack.If there is insufficient cross-linking, resultant PVP reservoir 114 doesnot retain shape, may detach from reinforcement 126 and is extremedifficult to handle. If the degree of cross-linking is too great, theresultant PVP reservoir 114 has insufficient tack to adhere to electrode112 or to patient contact area 122.

The use of the electron beam for cross-linking the PVP for reservoir 114has a particular benefit to the present invention. Unlike gammaradiation that has a potential penetration of several feet of concrete,the electron beam penetration depth is described in the units of cm ofwater. This property of the electron beam can be utilized in controllingthe degree of cross-link in reservoir 114. The exposure can becontrolled so that there is a differential degree of tack on surface 118than on surface 120 of reservoir 114. The differential degree of tack onthe first surface and the second surface may be preselected to allow asufficient degree of tack on surface 120 to ensure a sufficiently strongbond between electrode 112 and reservoir 114 to substantially preventseparation of the electrode and the reservoir while allowing thereservoir to be removed from the patient's skin.

The preferred degree of cross-link is determined by the degree of tackas described below. The preferred which results in a swelling ratio ofgreater than 3. Additionally, because the bibulous material isconstrained in the “x” and “y” directions by the reinforcement 126, bestseen in FIG. 6, the swelling that occurs upon imbibement of aqueoussolution, preferably occurs substantially only in the “z” direction,i.e., to increase the distance “d” between first surface 118 and secondsurface 120.

The manufacture of hydrophilic reservoir 114 is preferably begun with aweb of reinforcement 126 being coated on both sides with a viscoussolution of the PVP with a concentration of between about twenty percentto about thirty percent, preferably about 24 percent, (w/w) in anaqueous solution. When prepared in this fashion, the preferred PVPsolution has a viscosity similar to that of molasses and is adherent toreinforcement 126. As the coating of PVP is applied, web 126, with thecoating is preferably sandwiched between two release liners. Preferably,one of the release liners 130 is formed from a stiff polymeric material,such as PET coated with polyethylene or silicone and the like. Stiffrelease liner 130 serves as an anvil for die cutting out sections ofhydrophilic reservoir 114 in the shape desired for incorporation intothe iontophoretic device electrode reservoir assembly. Once the PVP iscoated onto reinforcement 126 and placed between the release liners, theentire web, i.e., reinforcement 126, the PVP coating and the releaseliners, is exposed to the preselected dose of ionizing radiation forcross-linking. Preferably, the thickness of the cross-linked material isbetween about 35 to about 45 mils. For particular applications, otherthickness may be preferred. Upon cross-linking, the reinforced PVPreservoir material preferably has a cohesive strength, a tackinesssufficient to adhere releasably to a patient's skin and to form anadhesive bond 124 with conductive ink electrode 112 on a flexiblesubstrate 140. Preferably, the adhesive bond formed between reservoir114 and conductive ink electrode 112 is stronger that the cohesivestrength of the cross-linked PVP used to form the reservoir. This strongbond between electrode 112 and reservoir 114 ensures good electricalcontact and substantially prevents the reservoir from detaching from theelectrode. Additionally, it is also preferred that the strength ofadhesive bond 124 formed between the reservoir 114 and conductive inkelectrode 112 is stronger than an adhesive bond formed between thesurface of the patient's skin and reservoir 114 and that the cohesivestrength of the reservoir is greater than the strength of the adhesivebond between the patient's skin and the reservoir. This substantiallyensures that when reservoir 114 is removed from the patient's skin, thereservoir is substantially removed from the patient's skin, leavingsubstantially no residue.

In addition to the PVP in aqueous solution, preferably, the coatingsolution may also include preservative materials to inhibit microbialgrowth such as para-benzoic acid (paraben) and the like. A suitablepreservative includes a series of mixed parabens including, methylparaben, ethyl paraben, n-propyl paraben, iso-propyl paraben, n-butylparaben and 2-phenoxyethanol and is sold under the tradename “Phenonip”by Nipa Laboratories, Wilm. Del. In the present invention, the materialhas been shown effective at substantially preventing microbial growth ata concentration of about one-percent in the 24% aqueous PVP solution. Afurther benefit of the radiation cross-linking of the PVP withpreservative is that the radiation dose used for cross-linking issufficient to substantially eliminate most microorganisms and thepresence of the preservative then substantially inhibits and furthergrowth after loading and during shelf storage.

A preferred technique for measuring tack is called described in an ASTMmethod No. D3121-94 entitled: “TACK ROLLING BALL METHOD” (TRBM). Thisstandardized test method utilizes a standard inclined trough thatdelivers a standard ball bearing onto the surface of the material beingtested. The ball is released from a standard height in the trough ontothe surface of the test material and a measurement is made of thedistance in mm that the ball rolls on the surface being tested. Thegreater the tack exhibited by the test material, the shorter thedistance the ball rolls. For the preferred cross-linked PVP used inreservoir 114, the TRBM values are preferably between about 15 mm toabout 40 mm. If the tack is substantially greater than the preferredvalue, reservoir 114 may lack cohesive strength and not be shaperetaining. If the tack is substantially less than the preferred value,there is insufficient adherence to the skin and to the electrode. Othermethods of measuring adhesive ability are also useful for characterizingthe preferred cross-linked PVP. These methods include the probe tack andpeel from steel. These tests are useful to characterize the cross-linkedhydrophilic polymeric material used to form reservoir 114. An empiricaldescription of the preferred material is that, when cut into discs ofthe a size about 5 square centimeters, the discs are sufficientlyadherent when loaded with the aqueous medicament to be lifted after agentle pressure with an index finger on the surface of the disc.

When cross-linked PVP as described above is used in an iontophoreticdevice of the invention, the PVP concentration is preferably abouttwenty-four percent w/w and after imbibement of an aqueous solution ofthe desired medicament to be delivered, the PVP concentration is aboutfifteen percent. Other reservoirs used in iontophoretic devices havesignificantly higher concentrations of materials required as carriers.The reservoir of the invention in having only about fifteen percent PVPprovides the an unexpected benefit to the art by allowing the reservoirto be physically smaller and to increase the efficiency of the drugdelivery by making the drug more available for delivery and to providesufficient tack to both patient skin and electrode to ensuresubstantially uniform electrical contact.

An example of a drug delivery system using the reservoir assembly of theinvention is prepared as follows. A solution of poly(vinylpyrolidone),(PVPK90-F BASF) at a concentration of 24% w/w containing 1% w/w mixedparabens (Phenonip, Nipa Laboratories) in 0.06% sodium chloride wasprepared. After thorough mixing the resultant viscous solution wascoated onto both sides, best seen in FIG. 7, of a reinforcement (Reemay2004, spun bonded polyester to a thickness of about 40 thousandths of aninch (40 mils). The coated reinforcement was applied to a release liner132 formed form low density polyethylene (LDPE) film on one side andstiffer laminate 130 of 2 mil polyester and 2 mil LDPE disposed so thatthe LDPE laminate was on the other side of the viscous solution. Thematerial was then exposed to electron beam irradiation with the LDPEfilm was closest to the source of the electron beam energy. A dosage ofabout 2 megarad was administered to the material causing the PVP tocross-link. LDPE film 132 was then removed from one side of the PVP andthe material was cut into the desired, best seen in FIGS. 6 and 8, fivesquare centimeter shapes for the active electrode. The material withlaminate release liner 132 remaining on the other side was bonded onexposed side 120 onto a flexible substrate coated with conductive inkelectrode 112 containing silver and silver chloride in a suitablevehicle covering between about 60% to about 90% of the surface are ofsubstrate 140 in the region where reservoir 114 is positioned,preferably about 90% of its surface with a loading of one and one halfto about five grams of ink per square centimeter of surface area. Bykeeping the coverage of the ink electrode below about 90%, directcontact between the patient's skin and the ink electrode issubstantially precluded. After cross-linked material 114 is bonded toflexible ink electrode 112, reservoir 114 is ready to be loaded with theaqueous drug solution.

Flexible ink electrode 112 containing silver and silver chloride isapplied to the flexible substrate to connect the power source to thereservoir 114. The ink preferably has a resistivity of less than about120 ohms per square. A suitable ink is available from E.I. du Pont deneumours, Wilm. Del. The terminology of “ohms per square” is developedfrom the thin film electrode art. A term “ohm-cm” is used to define thespecific resistance or resistivity of a material and is labeled by theGreek letter P(RHO). Since the metric system is the standard measuringused in laboratories. P is defined as the number for ohms resistancebetween parallel faces of a cubic centimeter of a material. Everymaterial has a specific conductivity, so P is different for eachmaterial. This term is also known as ohms per centimeter cubed. In thecase where the material is in the form of a thin (i.e., about 0.00025 cmto about 0.025 cm) the term is defined as ohms per square. This isdefined as the resistance of a square surface area of film and isindependent of the size of the square. In the first instance R=PL/A, inthe case of a film A=Wt, where t is the thickness of the film so thatnow R=PL/Wt, since L=W for any size square, this leads to R=P/t. As P isa constant for any given material, it is apparent that R variesinversely as the film thickness. As a consequence, when a resistance isspecified in ohms per square and the resistivity of the conductive inkor film is known, the effective film thickness is thus specified. In theinstant example, a preferred thickness is achieved with at loading ofbetween about one and one-half to about five grams of conductive ink persquare centimeter of surface for electrode 112 which provides aresistivity of less than about 120 ohms.

In the present example, an aqueous loading solution of 30% lidocaineHCl, 3% epinephrine, 30% glycerin, 0.05% sodium metabisulfite, 0.03%ethylene diamine tetraacetic acid, and 0.06% citric acid are used forthe loading solution. The medicaments for delivery are lidocaine HCl andepinephrine, the glycerin serves as a humectant, the other minorcomponents serve to enhance drug stability by chelating metal ions andserving as antioxidants. In order to load this solution onto thereservoir with electrode 112, laminate release liner 132 is removed fromside 118 of reservoir 114 and a three-hundred microliter aliquot of thisloading solution is applied to exposed surface 118, which is thencovered with a final cover that remains in place until the reservoir isapplied to a patient to protect the reservoir. Other aqueousformulations of other medicaments and other concentrations may beenvisioned for the electrode assembly of the invention and are to beconsidered within the scope of the invention. The electrode assembly 110of the invention when loaded with the aqueous medicament solutiondescribed above has demonstrated sufficient shelf stability when storedin a package formed from materials substantially resistant to thepassage of moisture and oxygen at accelerated, ambient and cycledtemperatures for two years.

A counter electrode assembly for the iontophoretic device of theinvention is formed by cutting a second shape from the cross-linked PVPwith a surface area of about 2.75 square centimeter area. A counterelectrode reservoir is assembled in the same fashion as the activeelectrode described above. This counter electrode reservoir ispreferably loaded with an aqueous solution containing about 30%glycerin, 1% mixed parabens, 0.06% sodium chloride. The aqueous carrierfor both of the solutions preferably meets the standard for purifiedwater in the USP XXXIII.

It has been shown that if the loading solutions are not loadedsubstantially uniformly across surface 118 of reservoir 114, thatlocalized thickness variations of the reservoir may develop in thecross-linked PVP with adverse effects on attachment to electrode 112 andsubsequent attachment to the patient. Additionally, the localizedconcentration differentials of chloride ion may facilitate deteriorationof the silver/silver chloride electrode. Therefore, it is preferred thatthe loading solutions be substantially uniformly loaded across surface118 of the electrode reservoir. For the active electrode containing thelidocaine and epinephrine, a loading level of about three hundredmicroliters is preferred for a five square centimeter, forty-thousandthsthick reservoir with a uncharged volume of about 0.5 cc resulting in acharged volume of about 0.8 cc. For the counter or return electrode withan area of about two and three-quarters square centimeter surface area,the preferred loading is about two hundred microliters of the aqueoussolution.

When the cross-linked PVP material is loaded with the aqueous chargingsolutions, the final PVP concentration of in the electrode is reducedfrom about twenty-four percent to about fifteen percent. Thecross-linked PVP swells to about one hundred fifty percent of itsuncharged volume, and because of the reinforcement, the swelling occursprimarily in the “z” direction or increases the thickness of thereservoir 114 about sixty percent.

The reservoir electrode of the invention is an improvement to the art ofiontophoretic electrode reservoirs. The reservoir is efficient in itsutilization of available drug. Medicaments known to be labile, such asepinephrine, have satisfactory shelf stability when incorporated intothe reservoir. Since the reservoir of the invention is flexible andadhesive, the reservoir electrode makes good uniform contact with thepatient's skin, minimizing any tendency for the current to concentrateat a particular point causing irritation or burns to the patient's skin.The reservoir electrode is easily prepared and its properties such asadhesion, size and medicament loading are easily adjustable duringmanufacture.

1-23. (canceled)
 24. An iontophoretic drug delivery device, comprising:an electrode assembly, comprising: a working reservoir situated inelectrically conductive relation to the electrode assembly, wherein theworking reservoir comprises an aqueous swollen cross-linked watersoluble polymer, lidocaine and epinephrine.
 25. The iontophoretic drugdelivery device of claim 24, wherein the iontophoretic drug deliverydevice is prepackaged as a ready to use device.
 26. The iontophoreticdrug delivery device of claim 24, wherein, as measured by weight % ofthe total weight of the working reservoir, epinephrine is present up to0.1 wt. %.
 27. The iontophoretic drug delivery device of claim 26,wherein the lidocaine is present up to 10 wt. %.
 28. The iontophoreticdrug delivery device of claim 27, the working reservoir furthercomprises: glycerin, sodium metabisulfite, and EDTA.
 29. Theiontophoretic drug delivery device of claim 28, wherein theconcentration of glycerin is up to 10 wt. %, the concentration of sodiummetabisulfite is up to 0.05 wt. %, and the concentration of EDTA is upto 0.01 wt. %.
 30. The iontophoretic drug delivery device of claim 27,wherein the iontophoretic drug delivery device is prepackaged as a readyto use device.
 31. The iontophoretic drug delivery device of claim 24,wherein the concentration of epinephrine, as measured in weight % of thetotal weight of the working reservoir, is about 0.1 wt. % and theconcentration of lidocaine is about 10 wt. %.
 32. The iontophoretic drugdelivery device of claim 31, the working reservoir further comprisesabout 10 wt. % glycerin, about 0.05 wt. % sodium metabisulfite, andabout 0.01 wt. % EDTA disodium.
 33. The iontophoretic drug deliverydevice of claim 24, wherein the electrode assembly further comprisesfrom one to three return electrodes and a working electrode.
 34. Theiontophoretic drug delivery device of claim 33, wherein the one to threereturn electrodes have a total surface area between 1 to 5 cm² andwherein the working electrode has a surface area between 2 to 10 cm².35. The iontophoretic drug delivery device of claim 24, wherein theworking reservoir further comprises at least one stabilizer.
 36. Theiontophoretic drug delivery device of claim 35, wherein at least onestabilizer is at least one of sodium metabisulphite and EDTA.
 37. Theiontophoretic drug delivery device of claim 35, wherein the workingreservoir further comprises at least one additive.
 38. The iontophoreticdrug delivery device of claim 37, wherein the additive is selected fromglycerin, propylene glycol, polyethylene glycol, and conductive salts.39. The iontophoretic drug delivery device of claim 24, wherein theaqueous swollen cross linked water soluble polymer acts as an adhesive.40. The iontophoretic drug delivery device of claim 39, wherein theaqueous swollen cross linked water soluble polymer is selected frompolyethylene oxide, polyvinyl pyrrolidone, polyvinyl alcohol, andpolyacrylimide. 41-68. (canceled)
 69. An iontophoretic drug deliverydevice, comprising: an electrode assembly, comprising: a workingreservoir situated in electrically conductive relation to the electrodeassembly, wherein the working reservoir comprises an aqueous swollencross-linked water soluble polymer, lidocaine and epinephrine; whereinthe iontophoretic drug delivery device is prepackaged as a ready to usedevice.
 70. (canceled)